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Immune Globulin (IVIG and SCIG)

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Proprietary Information of UnitedHealthcare. Copyright 2019 United HealthCare Services, Inc.

IMMUNE GLOBULIN (IVIG AND SCIG)

Instructions for Use

Table of Contents Page APPLICATION .......................................................... 1 COVERAGE RATIONALE ............................................. 1 APPLICABLE CODES ............................................... 11 BACKGROUND ....................................................... 24 CLINICAL EVIDENCE .............................................. 24 U.S. FOOD AND DRUG ADMINISTRATION .................. 31 CENTERS FOR MEDICARE AND MEDICAID SERVICES ... 32 REFERENCES ......................................................... 32 POLICY HISTORY/REVISION INFORMATION ............... 35 INSTRUCTIONS FOR USE ........................................ 36

COVERAGE RATIONALE

This policy refers to the following immune globulin (IG) products: • HyQvia • Gammagard S-D • Gammagard liquid • Cuvitru • Gamastan • Gamastan S-D • Gamunex-C • Carimune NF Nanofiltered • Privigen • Hizentra • Bivigam • Flebogamma Dif • Gamaplex • Octagam • Panzyga • Gammaked • Xembify

Diagnoses

Asthma (severe, persistent, high- dose steroid-dependent)

Autoimmune bullous diseases Autoimmune uveitis

UnitedHealthcare® Community Plan

Commercial Policy • Immune Globulin (IVIG and SCIG)

https://www.uhcprovider.com/content/dam/provider/docs/public/policies/comm-medical-drug/immune-globulin-ivig-scig.pdf


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Diagnoses Bone marrow transplantation (BMT) Chronic inflammatory

demyelinating polyneuropathy Chronic lymphocytic leukemia (CLL), prevention of infection in B-cell CLL

Cytomegalovirus (CMV) induced pneumonitis in solid organ transplants

Dermatomyositis or polymyositis Diabetes mellitus

Enteroviral meningoencephalitis Feto-neonatal alloimmune thrombocytopenia

Graves’ ophthalmopathy

Guillain-Barré syndrome (GBS) HIV-infection, prevention of bacterial infection in pediatric HIV

Immune thrombocytopenia

IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathy

Kawasaki disease Lambert-Eaton myasthenic syndrome (LEMS)

Lennox Gastaut syndrome Lymphoproliferative disease, treatment of bacterial infections

Monoclonal gammopathy

Multifocal motor neuropathy (MMN) Multiple sclerosis, relapsing forms Multiple myeloma, prevention of infection

Myasthenia gravis Neuromyeltis optica Paraproteinemic neuropathy Posttransfusion purpura Post B-cell targeted therapies Primary

immunodeficiency syndromes

Rasmussen syndrome Renal transplantation, prevention of acute humoral rejection

Rheumatoid arthritis, severe

Rotaviral enterocolitis Staphylococcal toxic shock Stiff-person syndrome Thrombocytopenia, secondary to HCV, HIV, or pregnancy

Toxic epidermal necrolysis or Stevens-Johnson syndrome

Urticaria, delayed pressure

Unproven uses

The Following Information Pertains to Medical Necessity Review General Requirements (Applicable to All Medical Necessity Requests) For initial therapy, all of the following: • Diagnosis; and • Medical records documenting all of the following:

o History and physical examination documenting the severity of the condition, including frequency and severity of infections where applicable; and

o Laboratory results or diagnostic evidence supporting the indication for which immune globulin is requested and

o Initial authorization will be for no more than 12 months • If the request is for a non-preferred product, there is a history of failure, contraindication or intolerance to 3

preferred products. Prior trials of formulary/PDL alternatives must sufficiently demonstrate that the formulary/PDL alternatives are either ineffective or inappropriate at the time of the request. NOTE: In instances where there are fewer than three preferred alternatives, the patient must have a history of failure, contraindication, or intolerance to all of the preferred products.

For continuation of therapy, all of the following: • Documentation of positive clinical response to immune globulin therapy; and • Statement of expected frequency and duration of proposed immune globulin treatment; and • For long term treatment, documentation of titration to the minimum effective dose and frequency needed to

maintain a sustained clinical response; and • Authorization will be for no more than 12 months

Diagnosis-Specific Requirements


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The information below indicates additional requirements for those indications having specific medical necessity criteria in the list of proven indications.

Immune globulin is proven for:

• Asthma (severe, persistent, high-dose steroid-dependent) 64-66

Immune globulin is medically necessary for the treatment of severe, persistent, high-dose steroid-dependent asthma when all of the following criteria are met: o Patient is receiving optimal conventional asthma therapy (e.g., high-dose inhaled glucocorticoids, short- and

long-acting inhaled β agonists); and


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o History of failure, contraindication, or intolerance at least two the following: Anti-IgE therapy [e.g., Xolair (omalizumab)] Anti-interleukin 4 therapy [e.g., Dupixent (dupilumab)] Anti-interleukin 5 therapy [e.g., Nucala (mepolizumab), Cinqair (resilizumab), Fasenra (benralizumab)] and

o Patient has required continuous oral glucocorticoid therapy for a minimum of 2 months prior to the decision to initiate immune globulin therapy; and

o For long term treatment, documentation of titration to the minimum dose and frequency needed to maintain a sustained clinical effect; and

o Prescribed by or in consultation with a pulmonologist or allergist/immunologist.

• Autoimmune bullous diseases [pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane (cicatricial) pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, linear IgA bullous dermatosis] 3,24,59 Immune globulin is medically necessary for the treatment of autoimmune bullous diseases when all of the following criteria are met: o Diagnosis of an autoimmune bullous disease; and o Extensive and debilitating disease; and o History of failure, contraindication, or intolerance to systemic corticosteroids with concurrent

immunosuppressive treatment (e.g., azathioprine, cyclophosphamide, mycophenolate mofetil); and o IVIG dose does not exceed 1,000 to 2,000 mg/kg per month divided into 3 equal doses each given over 3

consecutive days or 400 mg/kg per day given over 5 consecutive days per month. IVIG administration may be repeated monthly as needed for patients requiring maintenance therapy. Dosing interval may need to be adjusted in patients with severe comorbidities; 3 and

o For long term treatment, documentation of titration to the minimum dose and frequency needed to maintain a sustained clinical effect

• Autoimmune uveitis 59

• Bone marrow transplantation (BMT) 9,14,59,37

Immune globulin is medically necessary after allogeneic BMT when all of the following criteria are met: o One of the following uses: Prevention of acute graft vs. host disease (GVHD); or Prevention of infection; and

o Confirmed allogeneic bone marrow transplant within the last 100 days; and o Documented severe hypogammaglobulinemia (IgG < 400 mg/dL); and o IVIG dose does not exceed 500 mg/kg once weekly for the first 90 days of therapy, then monthly up to 360

days after transplantation

• Chronic inflammatory demyelinating polyneuropathy 8,17,30,35,37,40,59 Immune globulin is medically necessary for the treatment of chronic inflammatory demyelinating polyneuropathy when all of the following criteria are met: o Initial treatment:

Diagnosis of chronic inflammatory demyelinating polyneuropathy as confirmed by all of the following: - Progressive symptoms present for at least 2 months; and - Symptomatic polyradiculoneuropathy as indicated by progressive or relapsing motor or sensory

impairment of more than one limb; and - Electrodiagnostic findings (consistent with EFNS/PNS guidelines for definite CIDP) indicating at least

one of the following criteria are present: 68 • Motor distal latency prolongation in 2 nerves • Reduction of motor conduction velocity in 2 nerves • Prolongation of F-wave latency in 2 nerves • Absence of F-waves in at least 1 nerve • Partial motor conduction block of at least 1 motor nerve • Abnormal temporal dispersion in at least 2 nerves • Distal CMAP duration increase in at least 1 nerve;

and Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days administered in up

to six monthly infusions. Dosing interval may need to be adjusted in patients with severe comorbidities. o Continuation of treatment:


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Documentation of positive clinical response to therapy as measured by an objective scale [e.g., Rankin, Modified Rankin, Medical Research Council (MRC) scale]; and

For long-term treatment, documentation of titration to the minimum dose and frequency needed to maintain a sustained clinical effect; and

Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days. IVIG

administration may be repeated monthly as needed to prevent exacerbation. Dosing interval may need to be adjusted in patients with severe comorbidities.

• Chronic lymphocytic leukemia (CLL), prevention of infection in B-cell CLL 15,16,27,37

Immune globulin is medically necessary for the prevention of infection in B-cell chronic lymphocytic leukemia when all of the following criteria are met: o Diagnosis of B-cell chronic lymphocytic leukemia (CLL); and o One of the following:

Documented hypogammaglobulinemia (IgG < 500 mg/dL) History of bacterial infection(s) associated with B-cell CLL; and

o IVIG dose does not exceed 400 mg/kg every 3 to 4 weeks

• Cytomegalovirus (CMV) induced pneumonitis in solid organ transplants

• Dermatomyositis or polymyositis 8,9,30,59,62 Immune globulin is medically necessary for the treatment of dermatomyositis or polymyositis when all of the following criteria are met: o Diagnosis of dermatomyositis or polymyositis; and o History of failure, contraindication, or intolerance to immunosuppressive therapy (e.g., azathioprine,

corticosteroids, cyclophosphamide, methotrexate); and o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days administered as

monthly infusions. Dosing interval may need to be adjusted in patients with severe comorbidities; and o For long term treatment, documentation of titration to the minimum dose and frequency needed to maintain a

sustained clinical effect

• Diabetes mellitus 66-67 Immune globulin is medically necessary for the treatment of autoimmune diabetes mellitus when both of the following criteria are met: o Patient is newly diagnosed with insulin dependent (type 1) diabetes mellitus; and o Patient is not a candidate for or is refractory to insulin therapy

• Enteroviral meningoencephalitis 59

• Feto-neonatal alloimmune thrombocytopenia (AIT)1,32,79 Immune globulin is medically necessary for the treatment of feto-neonatal alloimmune thrombocytopenia when all of the following criteria are met: o For pregnant women:

Diagnosis of feto-neonatal alloimmune thrombocytopenia (AIT); and One or more of the following:

- Previously affected pregnancy - Family history of the disease - Platelet alloantibodies found on screening and

One of the following: - IVIG dose does not exceed 1,000 mg/kg once weekly until delivery; or - Both of the following:

• Fetus or newborn is considered to be at high risk for developing intracranial hemorrhage or other severe complication of AIT

• IVIG dose does not exceed 2,000 mg/kg once weekly until delivery or

o For newborns: Diagnosis of feto-neonatal alloimmune thrombocytopenia; and Thrombocytopenia that persists after transfusion of antigen-negative compatible platelets.

• Graves’ ophthalmopathy 59


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• Guillain-Barré syndrome (GBS) 8,30,40,59,62 Immune globulin is medically necessary for the treatment of Guillain-Barré syndrome when all of the following criteria are met: o Diagnosis of Guillain-Barré Syndrome; and o Severe disease requiring aid to walk; and o Onset of neuropathic symptoms within the last four weeks; and o Prescribed by or in consultation with a neurologist; and o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days. IVIG administration

may be repeated in up to three monthly infusions. Dosing interval may need to be adjusted in patients with severe comorbidities; and


• HIV-infection, prevention of bacterial infection in pediatric HIV 14,23,37

Immune globulin is medically necessary for the prevention of bacterial infection in pediatric HIV when all of the following criteria are met: o Diagnosis of HIV disease; and o Patient age ≤ 13 years; and o One of the following criteria: Documented hypogammaglobulinemia (IgG < 400 mg/dL); or Functional antibody deficiency as demonstrated by either poor specific antibody titers or recurrent

bacterial infections; and

o IVIG dose does not exceed 400 mg/kg every 28 days

• Immune thrombocytopenia [Idiopathic thrombocytopenic purpura (ITP)] 6,14,16,17,31,36,37,59 Immune globulin is medically necessary for the treatment of idiopathic thrombocytopenic purpura when at least one of the following criteria is met: o All of the following: Diagnosis of acute thrombocytopenic purpura (ITP); and Documented platelet count < 50 x 109 / L (obtained within the past 30 days); 36 and IVIG dose does not exceed 1,000 mg/kg/day for 1 to 2 days or

o All of the following: Diagnosis of chronic thrombocytopenic purpura (ITP); and History of failure, contraindication, or intolerance to at least one of the following:

- Corticosteroids - Splenectomy; and

IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days. IVIG administration may be repeated monthly as needed to prevent exacerbation. Dosing interval should be adjusted depending upon response and titrated to the minimum effective dose that can be given at maximum intervals to maintain safe platelet levels.

• IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathy 8,59

• Kawasaki disease 16,37,59

Immune globulin is medically necessary for the treatment of Kawasaki disease when both of the following criteria are met: o Diagnosis of Kawasaki disease; and o IVIG dose does not exceed 400 mg/kg for five consecutive days or a single dose of 2,000 mg/kg

• Lambert-Eaton myasthenic syndrome (LEMS) 8,9,30,47.59.62 Immune globulin is medically necessary for the treatment of Lambert-Eaton myasthenic syndrome when all of the following criteria are met: o Diagnosis of Lambert-Eaton myasthenic syndrome (LEMS); and o History of failure, contraindication, or intolerance to immunomodulator monotherapy (e.g., azathioprine,

corticosteroids); and o Concomitant immunomodulator therapy (e.g., azathioprine, corticosteroids), unless contraindicated, will be

used for long-term management of LEMS; and o Prescribed by or in consultation with a neurologist; and


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o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days. 62 IVIG administration may be repeated monthly as needed to prevent exacerbation. Dosing interval may need to be adjusted in patients with severe comorbidities; and


• Lennox Gastaut syndrome 9,62

Immune globulin is medically necessary for the treatment of Lennox Gastaut syndrome when all of the following criteria are met: o History of failure, contraindication or intolerance to initial treatment with traditional anti-epileptic

pharmacotherapy (e.g., lamotrigine, phenytoin, valproic acid); and o Prescribed by or in consultation with a neurologist; and o IVIG dose does not exceed 400 mg/kg/day given for 4 to 5 consecutive days. IVIG administration may be

repeated monthly as needed in patients requiring maintenance therapy. Dosing interval may need to be adjusted in patients with severe comorbidities; and


• Lymphoproliferative disease, treatment of bacterial infections 59

• Monoclonal gammopathy 59

• Multifocal motor neuropathy (MMN) 8,9,15,30,48,59,62

Immune globulin is medically necessary for the treatment of multifocal motor neuropathy when both of the following criteria are met: o Initial treatment:

Diagnosis of multifocal motor neuropathy as confirmed by all of the following: 48 - Weakness with slowly progressive or stepwise progressive course over at least one month; and - Asymmetric involvement of two or more nerves; and - Absence of motor neuron signs and bulbar signs; and

Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 2,400 mg/kg per month given over 2 to 5 consecutive days. IVIG

administration may be repeated monthly as needed to prevent exacerbation. Dosing interval may need to be adjusted in patients with severe comorbidities. 8,9,48,62

o Continuation of treatment: Documentation of positive clinical response to therapy as measured by an objective scale [e.g., Rankin,

Modified Rankin, Medical Research Council (MRC) scale]; and Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 2,400 mg/kg per month given over 2 to 5 consecutive days. Dosing interval

may need to be adjusted in patients with severe comorbidities; 8,9,48,62 and For long term treatment, documentation of titration to the minimum dose and frequency needed to

maintain a sustained clinical effect

• Multiple myeloma, prevention of infection in multiple myeloma75,77 Additional information to support medical necessity review where applicable: Immune globulin is medically necessary for the prevention of infection in multiple myeloma when ALL of the following criteria are met: o Diagnosis of multiple myeloma; and o One of the following: Documented hypogammaglobulinemia (IgG < 500 mg/dL) History of bacterial infection(s) associated with multiple myeloma and

o IVIG dose does not exceed 400 mg/kg every 3 to 4 weeks.

• Multiple sclerosis, relapsing forms 9,11,18,59,62 (Note: Treatment of any other type of multiple sclerosis with immune globulin is not supported by clinical evidence.) Immune globulin is medically necessary for the treatment of relapsing forms of multiple sclerosis when all of the following criteria are met: o Initial treatment:


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Diagnosis of relapsing forms of multiple sclerosis (MS) (e.g., relapsing-remitting MS, secondary- progressive MS with relapses, progressive-relapsing MS with relapses); and

Documentation of an MS exacerbation or progression (worsening) of the patient’s clinical status from the visit prior to the one prompting the decision to initiate immune globulin therapy; and

History of failure, contraindication, or intolerance to at least two of the following agents: - Aubagio (teriflunomide) - Avonex (interferon beta-1a) - Betaseron (interferon beta-1b) - Copaxone/Glatopa (glatiramer acetate) - Extavia (interferon beta-1b) - Gilenya (fingolimod) - Lemtrada (alemtuzumab) - Mavenclad (cladribine) - Mayzent (siponimod) - Ocrevus (ocrelizumab) - Plegridy (peginterferon beta-1a) - Rebif (interferon beta-1a) - Tecfidera (dimethyl fumarate) - Tysabri (natalizumab); and

Prescribed by or in consultation with a neurologist; and Induction, when indicated, does not exceed a dose of 400 mg/kg daily for up to five days

o Continuation of treatment: Medical records, including findings of interval examination including neurological deficits incurred and

assessment of disability [e.g., Expanded Disability Status Scale (EDSS), Functional Systems Score (FSS), Multiple Sclerosis Functional Composite (MSFC), Disease Steps (DS)]; and

Stable or improved disability score (e.g., EDSS, FSS, MSFC, DS); and Documentation of decreased number of relapses since starting immune globulin therapy; and Diagnosis continues to be the relapsing forms of MS; and Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 1,000 mg/kg monthly; and For long term treatment, documentation of titration to the minimum dose and frequency needed to

maintain a sustained clinical effect

• Myasthenia Gravis 8,9,13,20,30,59,62,69 (Note: Evidence does not support the use of immune globulin maintenance therapy for ocular myasthenia.) o Myasthenia Exacerbation

Immune globulin is medically necessary for the treatment of myasthenic exacerbation when all of the following criteria are met: Diagnosis of generalized myasthenia gravis; and Evidence of myasthenic exacerbation, defined by at least one of the following symptoms in the last month:

- Difficulty swallowing - Acute respiratory failure - Major functional disability responsible for the discontinuation of physical activity - Recent immunotherapy treatment with a checkpoint inhibitor [e.g., Keytruda (pembrolizumab),

Opdivo (nivolumab), Tecentriq (atezolizumab)]; and

One of the following: - History of failure, contraindication, or intolerance to immunomodulator therapy (e.g., azathioprine,

mycophenolate mofetil, cyclosporine) for long-term management of myasthenia gravis - Currently receiving immunomodulator therapy (e.g., azathioprine, mycophenolate mofetil,

cyclosporine) for long-term management of myasthenia gravis; and

Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days administered in up to three

monthly infusions. Dosing interval may need to be adjusted in patients with severe comorbidities. o Refractory Myasthenia Gravis

Immune globulin is medically necessary for the treatment of refractory myasthenia gravis when all of the following criteria are met: Diagnosis of refractory generalized myasthenia gravis by or in consultation with a physician or center with

expertise in management of myasthenia gravis; and


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Documentation that the disease status is unchanged or worsening (persistent or worsening symptoms that limit functioning) despite failure, contraindication, or intolerance to both of the following (used in adequate doses and duration): - Corticosteroids; and - Two immunomodulator therapies (e.g., azathioprine, mycophenolate mofetil, cyclosporine,

methotrexate, tacrolimus); and

Currently receiving immunomodulator therapy (e.g., corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, tacrolimus), used in adequate doses, for long-term management of myasthenia gravis; and

Prescribed by or in consultation with a neurologist; and IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days. Dosing interval may need to

be adjusted in patients with severe comorbidities.

• Neuromyeltis optica 22,55,56 Immune globulin is medically necessary for the treatment of neuromyelitis optica when all of the following criteria are met: Initial therapy o Submission of medical records (e.g., chart notes, laboratory values, etc.) to support the diagnosis of

neuromyelitis optica spectrum disorder (NMOSD) by a neurologist confirming all of the following: Serologic testing for anti-aquaporin-4 immunoglobulin G (AQP4-IgG)/NMO-IgG antibodies has been

performed; and Past medical history of (if AQP4-IgG/NMO-IgG positive one of the following, if negative two of the

following):25 - Optic neuritis - Acute myelitis - Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting - Acute brainstem syndrome - Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI

lesions - Symptomatic cerebral syndrome with NMOSD-typical brain lesions and

Diagnosis of multiple sclerosis or other diagnoses have been ruled out and

o Diagnosis of neuromyelitis optica; and o History of failure, contraindication, or intolerance to at least two of the following: Azathioprine Corticosteroids Mycophenolate mofetil Rituximab Soliris (eculizumab); and

o Patient is not receiving immune globulin in combination with either of the following: Rituximab Soliris (eculizumab)

o Prescribed by or in consultation with a neurologist; and o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days administered in up to six monthly

infusions. Dosing interval may need to be adjusted in patients with severe comorbidities.

Continuation therapy o Patient has previously been treated with immune globulin; and o Submission of medical records (e.g., chart notes, laboratory tests) to demonstrate a positive clinical response

from baseline as demonstrated by at least both of the following: Reduction in the number and/or severity of relapses or signs and symptoms of NMOSD Maintenance, reduction, or discontinuation of dose(s) of any baseline immunosuppressive therapy (IST)

prior to starting immune globulin. Note: Add on, dose escalation of IST, or additional rescue therapy from baseline to treat NMOSD or exacerbation of symptoms while on immune globulin therapy will be considered as treatment failure.

and o Patient is not receiving immune globulin in combination with either of the following: Rituximab Soliris (eculizumab)


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o Prescribed by or in consultation with a neurologist; and o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days administered in up to six monthly

infusions. Dosing interval may need to be adjusted in patients with severe comorbidities.

• Paraproteinemic neuropathy 59

• Posttransfusion purpura 3,59 Immune globulin is medically necessary for the treatment of posttransfusion purpura when both of the following criteria are met: o Diagnosis of posttransfusion purpura; and o IVIG dose does not exceed 1,000 mg/kg for 2 days

• Post B-Cell Targeted Therapies Immune globulin is medically necessary for the prevention of infection secondary to B-cell targeted therapy when all of the following criteria are met: o Documentation confirming previous treatment of B-cell targeted therapy within the last 100 days [e.g., CAR-T

(e.g., Kymriah), Rituxan (rituximab), Besponsa (inotuzumab ozogamicin)]; and o Both of the following:

Documented hypogammaglobulinemia (IgG < 500 mg/dL) History of bacterial infection(s) associated with B-cell depletion; and

o IVIG dose does not exceed 400 mg/kg every 4 weeks, up to 360 days after discontinuation of B-cell depleting therapy

• Primary immunodeficiency syndromes 3,6,12,14-17,21,28,31,37,42,43,48-54,59 (See disease list linked to below.)

Immune globulin is medically necessary for the treatment of primary immunodeficiency syndromes when all of the following criteria are met: o Diagnosis of primary immunodeficiency; and o Clinically significant functional deficiency of humoral immunity as evidenced by one of the following: Documented failure to produce antibodies to specific antigens; or History of significant recurrent infections; and

o Initial IVIG dose is 200 to 800 mg/kg every 3 to 4 weeks, based on product prescribing information, and titrated based upon patient response 28,51-2,57-61,,76,118,133 (For SCIG products, FDA-labeled dosing and conversion guidelines will used to determine benefit coverage.)

• Rasmussen syndrome59,62, 80

Immune globulin is medically necessary for the treatment of Rasmussen syndrome when BOTH of the following criteria are met: o Documentation of one of the following demonstrating that: Documentation that sShort term amelioration of encephalitis is needed prior to definitive surgical therapy; Disease symptoms (e.g., seizures) persist despite surgical treatment The patient is not a candidate for surgical treatment; and

o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days. IVIG is not recommended for long-term therapy for Rasmussen’s encephalitis as surgical treatment is the current standard of care.62

• Renal transplantation, prevention or treatment of acute humoral rejection 59

• Rheumatoid arthritis, severe 59

• Rotaviral enterocolitis 59

• Staphylococcal toxic shock 59

• Stiff-person syndrome 8,9,46,59,62

Immune globulin is medically necessary for the treatment of stiff-person syndrome when all of the following criteria are met: Initial treatment: o Diagnosis of stiff-person syndrome; and o History of failure, contraindication or intolerance to GABAergic medication (e.g., baclofen, benzodiazepines);

9,59,62 and


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o Prescribed by or in consultation with a neurologist; and o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days. IVIG administration may be

repeated monthly as needed for patients requiring maintenance therapy. Dosing interval may need to be adjusted in patients with severe comorbidities; 62 and

Continuation of treatment: o Documentation of a positive clinical improvement from baseline o Prescribed by or in consultation with a neurologist; and o IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 days. IVIG administration may be

repeated monthly as needed for patients requiring maintenance therapy. Dosing interval may need to be adjusted in patients with severe comorbidities62; and


• Thrombocytopenia, secondary to Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV), or

pregnancy 57 Immune globulin is medically necessary for the treatment of thrombocytopenia when one of the following criteria is met: o For initial therapy, all of the following:

One of the following: - Both of the following:

• Diagnosis of thrombocytopenia secondary to HCV infection • Patient is receiving concurrent antiviral therapy, unless contraindicated or

- Both of the following: • Diagnosis of thrombocytopenia secondary HIV infection • Patient is receiving concurrent antiviral therapy, unless contraindicated or

- Diagnosis of thrombocytopenia secondary to pregnancy; and

Documented platelet count < 50 x 109 / L (obtained within the past 30 days); 36 and IVIG dose does not exceed 1,000 mg/kg/day for 1 to 2 days or

o For continuation of therapy, both of the following: One of the following:

- Both of the following: • Diagnosis of thrombocytopenia secondary to HCV infection • Patient is receiving concurrent antiviral therapy, unless contraindicated or

- Both of the following: • Diagnosis of thrombocytopenia secondary to HIV infection • Patient is receiving concurrent antiviral therapy, unless contraindicated or

- Diagnosis of thrombocytopenia secondary to pregnancy; and

IVIG dose does not exceed 2,000 mg/kg per month given over 2 to 5 consecutive days. IVIG administration may be repeated monthly as needed to prevent exacerbation. Dosing interval should be adjusted depending upon response and titrated to the minimum effective dose that can be given at maximum intervals to maintain safe platelet levels.

• Toxic epidermal necrolysis or Stevens-Johnson syndrome 59

• Urticaria, delayed pressure 59

Immune globulin is unproven and not medically necessary for: • Acquired hemophilia • Acute disseminated encephalomyelitis (ADEM) • Adrenoleukodystrophy • Alzheimer’s disease • Amyotrophic lateral sclerosis (ALS) • Antiphospholipid antibody syndrome (APS) in pregnancy • Asthma, non-steroid dependent • Atopic dermatitis


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• Autism spectrum disorders • Autoimmune liver disease • Autoimmune neutropenia • Bone marrow transplantation (BMT), prevention of acute graft vs. host disease (GVHD) after autologous BMT • Bone marrow transplantation (BMT), prevention of chronic graft vs. host disease (GVHD) after autologous BMT • Bone marrow transplantation (BMT), prevention of infection after autologous BMT • Campylobacter species-induced enteritis • Cerebral infarctions with antiphospholipid antibodies • Chronic fatigue syndrome • Demyelinative brain stem encephalitis • Demyelinating neuropathy associated with monoclonal IgM • Dilated cardiomyopathy • HIV infection, to reduce viral load • HTLV-1-associated myelopathy • Idiopathic dysautonomia, acute • Inclusion body myositis • Isolated IgA deficiency • Isolated IgE deficiency • Isolated IgG4 deficiency • Isolated IgM deficiency • Lumbosacral or brachial plexitis • Myocarditis, acute • Neonatal isoimmune hemolytic jaundice • Neonatal sepsis, prevention • Ocular myasthenia • Opsoclonus myoclonus • Paraneoplastic cerebellar degeneration, sensory neuropathy, or encephalopathy • Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) • POEMS syndrome • Postinfectious cerebellar ataxia • Postoperative sepsis • Pseudomembranous colitis • Rheumatic fever, acute • Sjogren's syndrome • Spontaneous recurrent abortions, prevention • Urticaria, chronic • Vasculitides and antineutrophil antibody syndromes

Efficacy for these conditions has not been described in adequately designed studies. The available evidence is limited to case reports or case series, anecdotal reports, and open-label trials, or the available studies have failed to demonstrate a positive treatment effect. Further well-designed studies are needed to establish the role of immune globulin in these conditions.

APPLICABLE CODES

The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this policy does not imply that the service described by the code is a covered or non- covered health service. Benefit coverage for health services is determined by federal, state or contractual requirements and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Coverage Determination Guidelines may apply.

CPT Code Description

90283 Immune globulin (IgIV), human, for intravenous use 90284 Immune globulin (SCIg), human, for use in subcutaneous infusions, 100 mg, each

CPT® is a registered trademark of the American Medical Association

HCPCS Code Description

J1459 Injection, immune globulin (Privigen), intravenous, nonlyophilized (e.g., liquid), 500 mg J1555 Injection, immune globulin (Cuvitru), 100mg


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HCPCS Code Description J1556 Injection, immune globulin (Bivigam), 500 mg

J1557 Injection, immune globulin, (Gammaplex), intravenous, non-lyophilized (e.g., liquid), 500 mg J1559 Injection, immune globulin (Hizentra), 100 mg

J1561 Injection, immune globulin, (Gamunex-C/Gammaked), intravenous, nonlyophilized (e.g., liquid), 500 mg

J1566 Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg

J1568 Injection, immune globulin, (Octagam), intravenous, nonlyophilized (e.g., liquid), 500 mg

J1569 Injection, immune globulin, (Gammagard liquid), intravenous, nonlyophilized, (e.g., liquid), 500 mg

J1572 Injection, immune globulin, (Flebogamma/Flebogamma DIF), intravenous, nonlyophilized (e.g., liquid), 500 mg J1575 Injection, immune globulin/hyaluronidase, (Hyqvia), 100 mg immuneglobulin

J1599 Injection, immune globulin, intravenous, nonlyophilized (e.g., liquid), not otherwise specified, 500 mg

ICD-10 Diagnosis Code Description A08.0 Rotaviral enteritis A48.3 Toxic shock syndrome A49.9 Bacterial infection, unspecified A87.0 Enteroviral meningitis A87.8 Other viral meningitis A87.9 Viral meningitis, unspecified A88.0 Enteroviral exanthematous fever [Boston xanthema] A88.8 Other specified viral infections of central nervous system B20 Human immunodeficiency virus [HIV] disease

B25.0 Cytomegaloviral pneumonitis C90.00 Multiple myeloma not having achieved remission C90. 01 Multiple myeloma in remission C90. 02 Multiple myeloma in relapse C91.10 Chronic lymphocytic leukemia of B-cell type not having achieved remission C91.11 Chronic lymphocytic leukemia of B-cell type in remission C91.12 Chronic lymphocytic leukemia of B-cell type in relapse D47.2 Monoclonal gammopathy

D47.9 Neoplasm of uncertain behavior of lymphoid, hematopoietic and related tissue, unspecified D69.3 Immune thrombocytopenic purpura D69.51 Posttransfusion purpura D69.59 Other secondary thrombocytopenia D80.0 Hereditary hypogammaglobulinemia D80.1 Nonfamilial hypogammaglobulinemia D80.3 Selective deficiency of immunoglobulin G [IgG] subclasses D80.4 Selective deficiency of immunoglobulin M [IgM] D80.5 Immunodeficiency with increased immunoglobulin M [IgM]

D80.6 Antibody deficiency with near-normal immunoglobulins or with hyperimmunoglobulinemia D80.7 Transient hypogammaglobulinemia of infancy


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ICD-10 Diagnosis Code Description D81.0 Severe combined immunodeficiency [SCID] with reticular dysgenesis D81.1 Severe combined immunodeficiency [SCID] with low T- and B-cell numbers D81.2 Severe combined immunodeficiency [SCID] with low or normal B-cell numbers D81.6 Major histocompatibility complex class I deficiency D81.7 Major histocompatibility complex class II deficiency D81.89 Other combined immunodeficiencies D81.9 Combined immunodeficiency, unspecified D82.0 Wiskott-Aldrich syndrome D82.1 Di George's syndrome D82.4 Hyperimmunoglobulin E [IgE] syndrome

D83.0 Common variable immunodeficiency with predominant abnormalities of B-cell numbers and function

D83.1 Common variable immunodeficiency with predominant immunoregulatory T-cell disorders D83.2 Common variable immunodeficiency with autoantibodies to B- or T-cells D83.8 Other common variable immunodeficiencies D83.9 Common variable immunodeficiency, unspecified D84.8 Other specified immunodeficiencies D89.2 Hypergammaglobulinemia, unspecified D89.9 Disorder involving the immune mechanism, unspecified

D89.810 Acute graft-versus-host disease D89.812 Acute on chronic graft-versus-host disease D89.82 Autoimmune lymphoproliferative syndrome [ALPS] E05.00 Thyrotoxicosis with diffuse goiter without thyrotoxic crisis or storm E05.01 Thyrotoxicosis with diffuse goiter with thyrotoxic crisis or storm E10.10 Type 1 diabetes mellitus with ketoacidosis without coma E10.11 Type 1 diabetes mellitus with ketoacidosis with coma E10.21 Type 1 diabetes mellitus with diabetic nephropathy E10.22 Type 1 diabetes mellitus with diabetic chronic kidney disease E10.29 Type 1 diabetes mellitus with other diabetic kidney complication E10.311 Type 1 diabetes mellitus with unspecified diabetic retinopathy with macular edema E10.319 Type 1 diabetes mellitus with unspecified diabetic retinopathy without macular edema

E10.3211 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, right eye

E10.3212 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, left eye

E10.3213 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, bilateral

E10.3219 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy with macular edema, unspecified eye

E10.3291 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, right eye

E10.3292 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, left eye

E10.3293 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, bilateral

E10.3299 Type 1 diabetes mellitus with mild nonproliferative diabetic retinopathy without macular edema, unspecified eye


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ICD-10 Diagnosis Code Description

E10.3311 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, right eye

E10.3312 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, left eye

E10.3313 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, bilateral

E10.3319 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy with macular edema, unspecified eye

E10.3391 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, right eye

E10.3392 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, left eye

E10.3393 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, bilateral

E10.3399 Type 1 diabetes mellitus with moderate nonproliferative diabetic retinopathy without macular edema, unspecified eye

E10.3411 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, right eye

E10.3412 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, left eye

E10.3413 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, bilateral

E10.3419 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy with macular edema, unspecified eye

E10.3491 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, right eye

E10.3492 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, left eye

E10.3493 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, bilateral

E10.3499 Type 1 diabetes mellitus with severe nonproliferative diabetic retinopathy without macular edema, unspecified eye

E10.3511 Type 1 diabetes mellitus with proliferative diabetic retinopathy with macular edema, right eye

E10.3512 Type 1 diabetes mellitus with proliferative diabetic retinopathy with macular edema, left eye

E10.3513 Type 1 diabetes mellitus with proliferative diabetic retinopathy with macular edema, bilateral

E10.3519 Type 1 diabetes mellitus with proliferative diabetic retinopathy with macular edema, unspecified eye

E10.3591 Type 1 diabetes mellitus with proliferative diabetic retinopathy without macular edema, right eye

E10.3592 Type 1 diabetes mellitus with proliferative diabetic retinopathy without macular edema, left eye

E10.3593 Type 1 diabetes mellitus with proliferative diabetic retinopathy without macular edema, bilateral

E10.3599 Type 1 diabetes mellitus with proliferative diabetic retinopathy without macular edema, unspecified eye

E10.3521 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, right eye

E10.3522 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, left eye


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ICD-10 Diagnosis Code Description

E10.3523 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, bilateral

E10.3529 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment involving the macula, unspecified eye

E10.3531 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, right eye

E10.3532 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, left eye

E10.3533 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, bilateral

E10.3539 Type 1 diabetes mellitus with proliferative diabetic retinopathy with traction retinal detachment not involving the macula, unspecified eye

E10.3541 Type 1 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, right eye

E10.3542 Type 1 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, left eye

E10.3543 Type 1 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, bilateral

E10.3549 Type 1 diabetes mellitus with proliferative diabetic retinopathy with combined traction retinal detachment and rhegmatogenous retinal detachment, unspecified eye E10.3551 Type 1 diabetes mellitus with stable proliferative diabetic retinopathy, right eye E10.3552 Type 1 diabetes mellitus with stable proliferative diabetic retinopathy, left eye E10.3553 Type 1 diabetes mellitus with stable proliferative diabetic retinopathy, bilateral

E10.3559 Type 1 diabetes mellitus with stable proliferative diabetic retinopathy, unspecified eye

E10.37X1 Type 1 diabetes mellitus with diabetic macular edema, resolved following treatment, right eye

E10.37X2 Type 1 diabetes mellitus with diabetic macular edema, resolved following treatment, left eye

E10.37X3 Type 1 diabetes mellitus with diabetic macular edema, resolved following treatment, bilateral

E10.37X9 Type 1 diabetes mellitus with diabetic macular edema, resolved following treatment, unspecified eye E10.36 Type 1 diabetes mellitus with diabetic cataract E10.39 Type 1 diabetes mellitus with other diabetic ophthalmic complication E10.40 Type 1 diabetes mellitus with diabetic neuropathy, unspecified E10.41 Type 1 diabetes mellitus with diabetic mononeuropathy E10.42 Type 1 diabetes mellitus with diabetic polyneuropathy E10.43 Type 1 diabetes mellitus with diabetic autonomic (poly)neuropathy E10.44 Type 1 diabetes mellitus with diabetic amyotrophy E10.49 Type 1 diabetes mellitus with other diabetic neurological complication E10.51 Type 1 diabetes mellitus with diabetic peripheral angiopathy without gangrene E10.52 Type 1 diabetes mellitus with diabetic peripheral angiopathy with gangrene E10.59 Type 1 diabetes mellitus with other circulatory complications E10.610 Type 1 diabetes mellitus with diabetic neuropathic arthropathy E10.618 Type 1 diabetes mellitus with other diabetic arthropathy E10.620 Type 1 diabetes mellitus with diabetic dermatitis E10.621 Type 1 diabetes mellitus with foot ulcer E10.622 Type 1 diabetes mellitus with other skin ulcer E10.628 Type 1 diabetes mellitus with other skin complications


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ICD-10 Diagnosis Code Description E10.630 Type 1 diabetes mellitus with periodontal disease E10.638 Type 1 diabetes mellitus with other oral complications E10.641 Type 1 diabetes mellitus with hypoglycemia with coma E10.649 Type 1 diabetes mellitus with hypoglycemia without coma E10.65 Type 1 diabetes mellitus with hyperglycemia E10.69 Type 1 diabetes mellitus with other specified complication E10.8 Type 1 diabetes mellitus with unspecified complications E10.9 Type 1 diabetes mellitus without complications E31.0 Autoimmune polyglandular failure

G04.81 Other encephalitis and encephalomyelitis G04.90 Encephalitis and encephalomyelitis, unspecified G05.3 Encephalitis and encephalomyelitis in diseases classified elsewhere G05.4 Myelitis in diseases classified elsewhere G11.3 Cerebellar ataxia with defective DNA repair G25.82 Stiff-man syndrome

G35 Multiple sclerosis G36.0 Neuromyelitis optica [Devic]

G40.811 Lennox-Gastaut syndrome, not intractable, with status epilepticus G40.812 Lennox-Gastaut syndrome, not intractable, without status epilepticus G40.813 Lennox-Gastaut syndrome, intractable, with status epilepticus G40.814 Lennox-Gastaut syndrome, intractable, without status epilepticus G61.0 Guillain-Barré syndrome G61.81 Chronic inflammatory demyelinating polyneuritis G61.89 Other inflammatory polyneuropathies G61.9 Inflammatory polyneuropathy, unspecified G62.89 Other specified polyneuropathies G62.9 Polyneuropathy, unspecified G65.0 Sequelae of Guillain-Barré syndrome G70.00 Myasthenia gravis without (acute) exacerbation G70.01 Myasthenia gravis with (acute) exacerbation G70.80 Lambert-Eaton syndrome, unspecified G70.81 Lambert-Eaton syndrome in disease classified elsewhere G73.1 Lambert-Eaton syndrome in neoplastic disease H20.00 Unspecified acute and subacute iridocyclitis H20.011 Primary iridocyclitis, right eye H20.012 Primary iridocyclitis, left eye H20.013 Primary iridocyclitis, bilateral H20.019 Primary iridocyclitis, unspecified eye H20.021 Recurrent acute iridocyclitis, right eye H20.022 Recurrent acute iridocyclitis, left eye H20.023 Recurrent acute iridocyclitis, bilateral H20.029 Recurrent acute iridocyclitis, unspecified eye H20.041 Secondary noninfectious iridocyclitis, right eye H20.042 Secondary noninfectious iridocyclitis, left eye H20.043 Secondary noninfectious iridocyclitis, bilateral H20.049 Secondary noninfectious iridocyclitis, unspecified eye


Page 18 of 36


ICD-10 Diagnosis Code Description J45.51 Severe persistent asthma with (acute) exacerbation J45.52 Severe persistent asthma with status asthmaticus L10.0 Pemphigus vulgaris L10.2 Pemphigus foliaceous L12.0 Bullous pemphigoid L12.1 Cicatricial pemphigoid L12.30 Acquired epidermolysis bullosa, unspecified L12.35 Other acquired epidermolysis bullosa L13.8 Other specified bullous disorders L50.8 Other urticaria L51.1 Stevens-Johnson syndrome L51.2 Toxic epidermal necrolysis [Lyell] L51.3 Stevens-Johnson syndrome-toxic epidermal necrolysis overlap syndrome

M05.00 Felty's syndrome, unspecified site M05.011 Felty's syndrome, right shoulder M05.012 Felty's syndrome, left shoulder M05.019 Felty's syndrome, unspecified shoulder M05.021 Felty's syndrome, right elbow M05.022 Felty's syndrome, left elbow M05.029 Felty's syndrome, unspecified elbow M05.031 Felty's syndrome, right wrist M05.032 Felty's syndrome, left wrist M05.039 Felty's syndrome, unspecified wrist M05.041 Felty's syndrome, right hand M05.042 Felty's syndrome, left hand M05.049 Felty's syndrome, unspecified hand M05.051 Felty's syndrome, right hip M05.052 Felty's syndrome, left hip M05.059 Felty's syndrome, unspecified hip M05.061 Felty's syndrome, right knee M05.062 Felty's syndrome, left knee M05.069 Felty's syndrome, unspecified knee M05.071 Felty's syndrome, right ankle and foot M05.072 Felty's syndrome, left ankle and foot M05.079 Felty's syndrome, unspecified ankle and foot M05.09 Felty's syndrome, multiple sites M05.20 Rheumatoid vasculitis with rheumatoid arthritis of unspecified site M05.211 Rheumatoid vasculitis with rheumatoid arthritis of right shoulder M05.212 Rheumatoid vasculitis with rheumatoid arthritis of left shoulder M05.219 Rheumatoid vasculitis with rheumatoid arthritis of unspecified shoulder M05.221 Rheumatoid vasculitis with rheumatoid arthritis of right elbow M05.222 Rheumatoid vasculitis with rheumatoid arthritis of left elbow M05.229 Rheumatoid vasculitis with rheumatoid arthritis of unspecified elbow M05.231 Rheumatoid vasculitis with rheumatoid arthritis of right wrist M05.232 Rheumatoid vasculitis with rheumatoid arthritis of left wrist M05.239 Rheumatoid vasculitis with rheumatoid arthritis of unspecified wrist


Page 19 of 36


ICD-10 Diagnosis Code Description M05.241 Rheumatoid vasculitis with rheumatoid arthritis of right hand M05.242 Rheumatoid vasculitis with rheumatoid arthritis of left hand M05.249 Rheumatoid vasculitis with rheumatoid arthritis of unspecified hand M05.251 Rheumatoid vasculitis with rheumatoid arthritis of right hip M05.252 Rheumatoid vasculitis with rheumatoid arthritis of left hip M05.259 Rheumatoid vasculitis with rheumatoid arthritis of unspecified hip M05.261 Rheumatoid vasculitis with rheumatoid arthritis of right knee M05.262 Rheumatoid vasculitis with rheumatoid arthritis of left knee M05.269 Rheumatoid vasculitis with rheumatoid arthritis of unspecified knee M05.271 Rheumatoid vasculitis with rheumatoid arthritis of right ankle and foot M05.272 Rheumatoid vasculitis with rheumatoid arthritis of left ankle and foot M05.279 Rheumatoid vasculitis with rheumatoid arthritis of unspecified ankle and foot M05.29 Rheumatoid vasculitis with rheumatoid arthritis of multiple sites M05.30 Rheumatoid heart disease with rheumatoid arthritis of unspecified site M05.311 Rheumatoid heart disease with rheumatoid arthritis of right shoulder M05.312 Rheumatoid heart disease with rheumatoid arthritis of left shoulder M05.319 Rheumatoid heart disease with rheumatoid arthritis of unspecified shoulder M05.321 Rheumatoid heart disease with rheumatoid arthritis of right elbow M05.322 Rheumatoid heart disease with rheumatoid arthritis of left elbow M05.329 Rheumatoid heart disease with rheumatoid arthritis of unspecified elbow M05.331 Rheumatoid heart disease with rheumatoid arthritis of right wrist M05.332 Rheumatoid heart disease with rheumatoid arthritis of left wrist M05.339 Rheumatoid heart disease with rheumatoid arthritis of unspecified wrist M05.341 Rheumatoid heart disease with rheumatoid arthritis of right hand M05.342 Rheumatoid heart disease with rheumatoid arthritis of left hand M05.349 Rheumatoid heart disease with rheumatoid arthritis of unspecified hand M05.351 Rheumatoid heart disease with rheumatoid arthritis of right hip M05.352 Rheumatoid heart disease with rheumatoid arthritis of left hip M05.359 Rheumatoid heart disease with rheumatoid arthritis of unspecified hip M05.361 Rheumatoid heart disease with rheumatoid arthritis of right knee M05.362 Rheumatoid heart disease with rheumatoid arthritis of left knee M05.369 Rheumatoid heart disease with rheumatoid arthritis of unspecified knee M05.371 Rheumatoid heart disease with rheumatoid arthritis of right ankle and foot M05.372 Rheumatoid heart disease with rheumatoid arthritis of left ankle and foot M05.379 Rheumatoid heart disease with rheumatoid arthritis of unspecified ankle and foot M05.39 Rheumatoid heart disease with rheumatoid arthritis of multiple sites M05.40 Rheumatoid myopathy with rheumatoid arthritis of unspecified site M05.411 Rheumatoid myopathy with rheumatoid arthritis of right shoulder M05.412 Rheumatoid myopathy with rheumatoid arthritis of left shoulder M05.419 Rheumatoid myopathy with rheumatoid arthritis of unspecified shoulder M05.421 Rheumatoid myopathy with rheumatoid arthritis of right elbow M05.422 Rheumatoid myopathy with rheumatoid arthritis of left elbow M05.429 Rheumatoid myopathy with rheumatoid arthritis of unspecified elbow M05.431 Rheumatoid myopathy with rheumatoid arthritis of right wrist M05.432 Rheumatoid myopathy with rheumatoid arthritis of left wrist M05.439 Rheumatoid myopathy with rheumatoid arthritis of unspecified wrist


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ICD-10 Diagnosis Code Description M05.441 Rheumatoid myopathy with rheumatoid arthritis of right hand M05.442 Rheumatoid myopathy with rheumatoid arthritis of left hand M05.449 Rheumatoid myopathy with rheumatoid arthritis of unspecified hand M05.451 Rheumatoid myopathy with rheumatoid arthritis of right hip M05.452 Rheumatoid myopathy with rheumatoid arthritis of left hip M05.459 Rheumatoid myopathy with rheumatoid arthritis of unspecified hip M05.461 Rheumatoid myopathy with rheumatoid arthritis of right knee M05.462 Rheumatoid myopathy with rheumatoid arthritis of left knee M05.469 Rheumatoid myopathy with rheumatoid arthritis of unspecified knee M05.471 Rheumatoid myopathy with rheumatoid arthritis of right ankle and foot M05.472 Rheumatoid myopathy with rheumatoid arthritis of left ankle and foot M05.479 Rheumatoid myopathy with rheumatoid arthritis of unspecified ankle and foot M05.49 Rheumatoid myopathy with rheumatoid arthritis of multiple sites M05.50 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified site M05.511 Rheumatoid polyneuropathy with rheumatoid arthritis of right shoulder M05.512 Rheumatoid polyneuropathy with rheumatoid arthritis of left shoulder M05.519 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified shoulder M05.521 Rheumatoid polyneuropathy with rheumatoid arthritis of right elbow M05.522 Rheumatoid polyneuropathy with rheumatoid arthritis of left elbow M05.529 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified elbow M05.531 Rheumatoid polyneuropathy with rheumatoid arthritis of right wrist M05.532 Rheumatoid polyneuropathy with rheumatoid arthritis of left wrist M05.539 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified wrist M05.541 Rheumatoid polyneuropathy with rheumatoid arthritis of right hand M05.542 Rheumatoid polyneuropathy with rheumatoid arthritis of left hand M05.549 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified hand M05.551 Rheumatoid polyneuropathy with rheumatoid arthritis of right hip M05.552 Rheumatoid polyneuropathy with rheumatoid arthritis of left hip M05.559 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified hip M05.561 Rheumatoid polyneuropathy with rheumatoid arthritis of right knee M05.562 Rheumatoid polyneuropathy with rheumatoid arthritis of left knee M05.569 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified knee M05.571 Rheumatoid polyneuropathy with rheumatoid arthritis of right ankle and foot M05.572 Rheumatoid polyneuropathy with rheumatoid arthritis of left ankle and foot M05.579 Rheumatoid polyneuropathy with rheumatoid arthritis of unspecified ankle and foot M05.59 Rheumatoid polyneuropathy with rheumatoid arthritis of multiple sites

M05.60 Rheumatoid arthritis of unspecified site with involvement of other organs and systems M05.611 Rheumatoid arthritis of right shoulder with involvement of other organs and systems M05.612 Rheumatoid arthritis of left shoulder with involvement of other organs and systems

M05.619 Rheumatoid arthritis of unspecified shoulder with involvement of other organs and systems M05.621 Rheumatoid arthritis of right elbow with involvement of other organs and systems M05.622 Rheumatoid arthritis of left elbow with involvement of other organs and systems

M05.629 Rheumatoid arthritis of unspecified elbow with involvement of other organs and systems M05.631 Rheumatoid arthritis of right wrist with involvement of other organs and systems


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ICD-10 Diagnosis Code Description M05.632 Rheumatoid arthritis of left wrist with involvement of other organs and systems

M05.639 Rheumatoid arthritis of unspecified wrist with involvement of other organs and systems M05.641 Rheumatoid arthritis of right hand with involvement of other organs and systems M05.642 Rheumatoid arthritis of left hand with involvement of other organs and systems

M05.649 Rheumatoid arthritis of unspecified hand with involvement of other organs and systems M05.651 Rheumatoid arthritis of right hip with involvement of other organs and systems M05.652 Rheumatoid arthritis of left hip with involvement of other organs and systems M05.659 Rheumatoid arthritis of unspecified hip with involvement of other organs and systems M05.661 Rheumatoid arthritis of right knee with involvement of other organs and systems M05.662 Rheumatoid arthritis of left knee with involvement of other organs and systems

M05.669 Rheumatoid arthritis of unspecified knee with involvement of other organs and systems

M05.671 Rheumatoid arthritis of right ankle and foot with involvement of other organs and systems

M05.672 Rheumatoid arthritis of left ankle and foot with involvement of other organs and systems

M05.679 Rheumatoid arthritis of unspecified ankle and foot with involvement of other organs and systems M05.69 Rheumatoid arthritis of multiple sites with involvement of other organs and systems

M05.70 Rheumatoid arthritis with rheumatoid factor of unspecified site without organ or systems involvement

M05.711 Rheumatoid arthritis with rheumatoid factor of right shoulder without organ or systems involvement

M05.712 Rheumatoid arthritis with rheumatoid factor of left shoulder without organ or systems involvement

M05.719 Rheumatoid arthritis with rheumatoid factor of unspecified shoulder without organ or systems involvement M06.1 Adult-onset Still's disease M08.00 Unspecified juvenile rheumatoid arthritis of unspecified site M08.011 Unspecified juvenile rheumatoid arthritis, right shoulder M08.012 Unspecified juvenile rheumatoid arthritis, left shoulder M08.019 Unspecified juvenile rheumatoid arthritis, unspecified shoulder M08.021 Unspecified juvenile rheumatoid arthritis, right elbow M08.022 Unspecified juvenile rheumatoid arthritis, left elbow M08.029 Unspecified juvenile rheumatoid arthritis, unspecified elbow M08.031 Unspecified juvenile rheumatoid arthritis, right wrist M08.032 Unspecified juvenile rheumatoid arthritis, left wrist M08.039 Unspecified juvenile rheumatoid arthritis, unspecified wrist M08.041 Unspecified juvenile rheumatoid arthritis, right hand M08.042 Unspecified juvenile rheumatoid arthritis, left hand M08.049 Unspecified juvenile rheumatoid arthritis, unspecified hand M08.051 Unspecified juvenile rheumatoid arthritis, right hip M08.052 Unspecified juvenile rheumatoid arthritis, left hip M08.059 Unspecified juvenile rheumatoid arthritis, unspecified hip M08.061 Unspecified juvenile rheumatoid arthritis, right knee M08.062 Unspecified juvenile rheumatoid arthritis, left knee M08.069 Unspecified juvenile rheumatoid arthritis, unspecified knee


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ICD-10 Diagnosis Code Description M08.071 Unspecified juvenile rheumatoid arthritis, right ankle and foot M08.072 Unspecified juvenile rheumatoid arthritis, left ankle and foot M08.079 Unspecified juvenile rheumatoid arthritis, unspecified ankle and foot M08.08 Unspecified juvenile rheumatoid arthritis, vertebrae M08.09 Unspecified juvenile rheumatoid arthritis, multiple sites M08.20 Juvenile rheumatoid arthritis with systemic onset, unspecified site M08.211 Juvenile rheumatoid arthritis with systemic onset, right shoulder M08.212 Juvenile rheumatoid arthritis with systemic onset, left shoulder M08.219 Juvenile rheumatoid arthritis with systemic onset, unspecified shoulder M08.221 Juvenile rheumatoid arthritis with systemic onset, right elbow M08.222 Juvenile rheumatoid arthritis with systemic onset, left elbow M08.229 Juvenile rheumatoid arthritis with systemic onset, unspecified elbow M08.231 Juvenile rheumatoid arthritis with systemic onset, right wrist M08.232 Juvenile rheumatoid arthritis with systemic onset, left wrist M08.239 Juvenile rheumatoid arthritis with systemic onset, unspecified wrist M08.241 Juvenile rheumatoid arthritis with systemic onset, right hand M08.242 Juvenile rheumatoid arthritis with systemic onset, left hand M08.249 Juvenile rheumatoid arthritis with systemic onset, unspecified hand M08.251 Juvenile rheumatoid arthritis with systemic onset, right hip M08.252 Juvenile rheumatoid arthritis with systemic onset, left hip M08.259 Juvenile rheumatoid arthritis with systemic onset, unspecified hip M08.261 Juvenile rheumatoid arthritis with systemic onset, right knee M08.262 Juvenile rheumatoid arthritis with systemic onset, left knee M08.269 Juvenile rheumatoid arthritis with systemic onset, unspecified knee M08.271 Juvenile rheumatoid arthritis with systemic onset, right ankle and foot M08.272 Juvenile rheumatoid arthritis with systemic onset, left ankle and foot M08.279 Juvenile rheumatoid arthritis with systemic onset, unspecified ankle and foot M08.28 Juvenile rheumatoid arthritis with systemic onset, vertebrae M08.29 Juvenile rheumatoid arthritis with systemic onset, multiple sites M08.3 Juvenile rheumatoid polyarthritis (seronegative) M08.40 Pauciarticular juvenile rheumatoid arthritis, unspecified site M08.411 Pauciarticular juvenile rheumatoid arthritis, right shoulder M08.412 Pauciarticular juvenile rheumatoid arthritis, left shoulder M08.419 Pauciarticular juvenile rheumatoid arthritis, unspecified shoulder M08.421 Pauciarticular juvenile rheumatoid arthritis, right elbow M08.422 Pauciarticular juvenile rheumatoid arthritis, left elbow M08.429 Pauciarticular juvenile rheumatoid arthritis, unspecified elbow M08.431 Pauciarticular juvenile rheumatoid arthritis, right wrist M08.432 Pauciarticular juvenile rheumatoid arthritis, left wrist M08.439 Pauciarticular juvenile rheumatoid arthritis, unspecified wrist M08.441 Pauciarticular juvenile rheumatoid arthritis, right hand M08.442 Pauciarticular juvenile rheumatoid arthritis, left hand M08.449 Pauciarticular juvenile rheumatoid arthritis, unspecified hand M08.451 Pauciarticular juvenile rheumatoid arthritis, right hip M08.452 Pauciarticular juvenile rheumatoid arthritis, left hip M08.459 Pauciarticular juvenile rheumatoid arthritis, unspecified hip


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ICD-10 Diagnosis Code Description M08.461 Pauciarticular juvenile rheumatoid arthritis, right knee M08.462 Pauciarticular juvenile rheumatoid arthritis, left knee M08.469 Pauciarticular juvenile rheumatoid arthritis, unspecified knee M08.471 Pauciarticular juvenile rheumatoid arthritis, right ankle and foot M08.472 Pauciarticular juvenile rheumatoid arthritis, left ankle and foot M08.479 Pauciarticular juvenile rheumatoid arthritis, unspecified ankle and foot M08.48 Pauciarticular juvenile rheumatoid arthritis, vertebrae M08.80 Other juvenile arthritis, unspecified site M08.811 Other juvenile arthritis, right shoulder M08.812 Other juvenile arthritis, left shoulder M08.819 Other juvenile arthritis, unspecified shoulder M08.821 Other juvenile arthritis, right elbow M08.822 Other juvenile arthritis, left elbow M08.829 Other juvenile arthritis, unspecified elbow M08.831 Other juvenile arthritis, right wrist M08.832 Other juvenile arthritis, left wrist M08.839 Other juvenile arthritis, unspecified wrist M08.841 Other juvenile arthritis, right hand M08.842 Other juvenile arthritis, left hand M08.849 Other juvenile arthritis, unspecified hand M08.851 Other juvenile arthritis, right hip M08.852 Other juvenile arthritis, left hip M08.859 Other juvenile arthritis, unspecified hip M08.861 Other juvenile arthritis, right knee M08.862 Other juvenile arthritis, left knee M08.869 Other juvenile arthritis, unspecified knee M08.871 Other juvenile arthritis, right ankle and foot M08.872 Other juvenile arthritis, left ankle and foot M08.879 Other juvenile arthritis, unspecified ankle and foot M08.88 Other juvenile arthritis, vertebrae M08.89 Other juvenile arthritis, multiple sites M08.90 Juvenile arthritis, unspecified, unspecified site M08.911 Juvenile arthritis, unspecified, right shoulder M08.912 Juvenile arthritis, unspecified, left shoulder M08.919 Juvenile arthritis, unspecified, unspecified shoulder M08.921 Juvenile arthritis, unspecified, right elbow M08.922 Juvenile arthritis, unspecified, left elbow M08.929 Juvenile arthritis, unspecified, unspecified elbow M08.931 Juvenile arthritis, unspecified, right wrist M08.932 Juvenile arthritis, unspecified, left wrist M08.939 Juvenile arthritis, unspecified, unspecified wrist M08.941 Juvenile arthritis, unspecified, right hand M08.942 Juvenile arthritis, unspecified, left hand M08.949 Juvenile arthritis, unspecified, unspecified hand M08.951 Juvenile arthritis, unspecified, right hip M08.952 Juvenile arthritis, unspecified, left hip


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ICD-10 Diagnosis Code Description M08.959 Juvenile arthritis, unspecified, unspecified hip M08.961 Juvenile arthritis, unspecified, right knee M08.962 Juvenile arthritis, unspecified, left knee M08.969 Juvenile arthritis, unspecified, unspecified knee M08.971 Juvenile arthritis, unspecified, right ankle and foot M08.972 Juvenile arthritis, unspecified, left ankle and foot M08.979 Juvenile arthritis, unspecified, unspecified ankle and foot M08.98 Juvenile arthritis, unspecified, vertebrae M08.99 Juvenile arthritis, unspecified, multiple sites M30.3 Mucocutaneous lymph node syndrome [Kawasaki] M33.00 Juvenile dermatomyositis, organ involvement unspecified M33.01 Juvenile dermatomyositis with respiratory involvement M33.02 Juvenile dermatomyositis with myopathy M33.03 Juvenile dermatomyositis without myopathy M33.09 Juvenile dermatomyositis with other organ involvement M33.10 Other dermatomyositis, organ involvement unspecified M33.11 Other dermatomyositis with respiratory involvement M33.12 Other dermatomyositis with myopathy M33.13 Other dermatomyositis without myopathy M33.19 Other dermatomyositis with other organ involvement M33.20 Polymyositis, organ involvement unspecified M33.21 Polymyositis with respiratory involvement M33.22 Polymyositis with myopathy M33.29 Polymyositis with other organ involvement M33.90 Dermatopolymyositis, unspecified, organ involvement unspecified M33.91 Dermatopolymyositis, unspecified with respiratory involvement M33.92 Dermatopolymyositis, unspecified with myopathy M33.93 Dermatopolymyositis, unspecified without myopathy M33.99 Dermatopolymyositis, unspecified with other organ involvement M36.0 Dermato(poly)myositis in neoplastic disease O26.40 Herpes gestationis, unspecified trimester O26.41 Herpes gestationis, first trimester O26.42 Herpes gestationis, second trimester O26.43 Herpes gestationis, third trimester P61.0 Transient neonatal thrombocytopenia T86.00 Unspecified complication of bone marrow transplant T86.01 Bone marrow transplant rejection T86.02 Bone marrow transplant failure T86.03 Bone marrow transplant infection T86.09 Other complications of bone marrow transplant T86.10 Unspecified complication of kidney transplant T86.11 Kidney transplant rejection T86.12 Kidney transplant failure T86.13 Kidney transplant infection T86.19 Other complication of kidney transplant Z29.8 Encounter for other specified prophylactic measures


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ICD-10 Diagnosis Code Description Z29.9 Encounter for prophylactic measures, unspecified

Z48.290 Encounter for aftercare following bone marrow transplant Z86.19 Personal history of other infectious and parasitic diseases

Z86.2 Personal history of diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism Z92.22 Personal history of monoclonal drug therapy Z92.29 Personal history of other drug therapy Z94.81 Bone marrow transplant status Z94.84 Stem cells transplant status

BACKGROUND

Immune globulin, whether intravenous (IV) or subcutaneous (SC), is a sterile, purified preparation of human immunoglobulin derived from pooled human plasma from thousands of donors. Consisting primarily of immunoglobulin G, one of 5 classes of immunoglobulin (Ig), each batch of immune globulin (typically referred to as IVIG) provides immunomodulating peptides and antibodies against most exogenous antigens, many normal human proteins, and Fab, the antigen-binding region of autoantibodies. 20 All currently available products contain high concentrations of IgG with subclass distribution corresponding to that of normal serum. 6,12,14-17,21,28,31,42,43,58

IVIG is considered a mainstay of treatment for immunodeficiency conditions and bullous skin disorders. It has been prescribed off-label to treat a wide variety of autoimmune and inflammatory neurologic conditions. 20

CLINICAL EVIDENCE

Proven Autoimmune Diseases IVIG is beneficial for treatment of a number of autoimmune diseases based upon US Food and Drug Administration (FDA) approval, published practice guidelines, professional society evidence reviews, and/or randomized, controlled clinical trials. These include immune thrombocytopenic purpura, 6,14,16,17,31,36,37,59 Graves’ ophthalmopathy, 59 autoimmune uveitis, 59 dermatomyositis and polymyositis, 8,9,30,59,62 severe rheumatoid arthritis, 59 and autoimmune diabetes mellitus. 59

IVIG is a first-line therapy for fetomaternal alloimmune thrombocytopenia. 32

An article by Anderson et al. summarized the National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services panel of national experts’ evidence-based practice guideline on the use of IVIG for hematologic conditions. Response rates in available reports of post-transfusion purpura, a rare and life-threatening condition were high. 8

Infectious and Infection-Related Diseases IVIG is beneficial for a number of infectious and infection-related diseases based upon FDA approval, published practice guidelines, professional society evidence reviews, and/or randomized, controlled clinical trials. These include prevention of coronary artery aneurysms associated with Kawasaki syndrome, 16,37,59 treatment of CMV-induced pneumonitis in solid organ transplants, 58 treatment of rotaviral enterocolitis, 59 treatment of staphylococcal toxic shock, 59 treatment of enteroviral meningoencephalitis, 59 treatment of bacterial infections in lymphoproliferative diseases, 59 prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell chronic lymphocytic leukemia (CLL). 16,27,37

Neuroimmunologic Disorders In 2016, the Myastenia Gravis Foundation of America published consensus based guidance for the management of myasthenia gravis (MG).69 Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy. In regards to the use of IVIG, the task force concluded: • Patients with refractory MG should be referred to a physician or a center with expertise in management of MG. In

addition to immunosuppressant agents, chronic IVIG may also be used. • IVIG is appropriately used as short-term treatments in patients with MG with lifethreatening signs such as

respiratory insufficiency or dysphagia; in preparation for surgery in patients with significant bulbar dysfunction;


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when a rapid response to treatment is needed; when other treatments are insufficiently effective; and prior to beginning corticosteroids if deemed necessary to prevent or minimize exacerbations.

• IVIG and PLEX are probably equally effective in the treatment of severe generalized MG. • The efficacy of IVIG is less certain in milder MG or in ocular MG. • PLEX may be more effective than IVIG in MuSK-MG. • The use of IVIG as maintenance therapy can be considered for patients with refractory MG or for those in whom

IS agents are relatively contraindicated.

In 2010, the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) published clinical guidelines for the management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).68 In regards to the diagnosis and treatment of CIDP with IVIG, the task force concluded: • For induction of treatment, IVIG should be considered in sensory and motor CIDP in the presence of disabling

symptoms (level A recommendation). • For maintenance treatment, there is no sufficient evidence to recommend any particular drug. If response to IVIG

is inadequate or result in adverse events, then other first-line treatment alternatives should be considered before combination treatments.

Electrodiagnostic Criteria: • Definite – At least one of the following:

o Motor distal latency prolongation ≥50% above ULN in two nerves (excluding median neuropathy at the wrist from carpal tunnel syndrome), or

o Reduction of motor conduction velocity ≥30% below LLN in two nerves, or o Prolongation of F-wave latency ≥30% above ULN in two nerves (≥50% if amplitude of distal negative peak

CMAP 30% duration increase between the proximal and distal negative peak CMAP) in ≥2 nerves, or

o Distal CMAP duration (interval between onset of the first negative peak and return to baseline of the last negative peak) increase in ≥1 nerve (median ≥ 6.6 ms, ulnar ≥ 6.7 ms, peroneal ≥ 7.6 ms, tibial ≥ 8.8 ms)b + ≥1 other demyelinating parametera in ≥1 other nerve

Clinical Diagnostic Criteria: • Inclusion Criteria:

(a) Typical CIDP: Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory

dysfunction of all extremities, developing over at least 2 months; cranial nerves may be affected; and Absent or reduced tendon reflexes in all extremities

(b) Atypical CIDP (still considered CIDP but with different features): One of the following, but otherwise as in (a) (tendon reflexes may be normal in unaffected limbs):

- Predominantly distal (distal acquired demyelinating symmetric, DADS), or - Asymmetric [multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), Lewis–

Sumner syndrome], or - Focal (e.g., involvement of the brachial or lumbosacral plexus or of one or more peripheral nerves in

one upper or lower limb), or - Pure motor, or - Pure sensory (including chronic immune sensory polyradiculopathy affecting the central process of the

primary sensory neuron) • Exclusion Criteria:

o Borrelia burgdorferi infection (Lyme disease), diphtheria, drug or toxin exposure probably to have caused the neuropathy

o Hereditary demyelinating neuropathy o Prominent sphincter disturbance o Diagnosis of multifocal motor neuropathy o IgM monoclonal gammopathy with high titre antibodies to myelin-associated glycoprotein o Other causes for a demyelinating neuropathy including POEMS syndrome, osteosclerotic myeloma, diabetic

and non-diabetic lumbosacral radiculoplexus neuropathy. PNS lymphoma and amyloidosis may occasionally have demyelinating features


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IVIG is beneficial for treatment of a number of neuroimmunologic diseases based upon FDA approval, published practice guidelines, professional society evidence reviews, and/or randomized, controlled clinical trials. These include chronic inflammatory demyelinating polyneuropathy, 8,17,30,35,37,40,59 Guillain-Barré syndrome, 8,30,41,59,62 multifocal motor neuropathy, 8,9,15,30,59,62 Lambert-Eaton myasthenic syndrome, 8,9,30,59,62 IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathy,59 paraproteinemic neuropathy,59 stiff-person syndrome, 8,9, 59 myasthenia gravis, 8,9,13,20,59,62Lennox-Gastaut, 9,62 Rasmussen syndrome, 59,62 and monoclonal gammopathy.

The National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services panel of national experts’ evidence-based practice guideline on the use of IVIG for neurologic conditions states that IVIG should be reserved as an option for patients with relapsing-remitting MS who fail, decline, or are not able to take standard immunomodulatory therapies. Based on consensus by the expert panel, IVIG is not recommended for treatment of primary or secondary progressive MS or for acute exacerbations of MS. 62

In their Guidelines for the Use of Intravenous Immunoglobulin in the Treatment of Neurological Diseases, the European Federation of Neurological Associations (EFNA) states that IVIG could be considered as a second or third- line therapy in RRMS if conventional immunomodulatory therapies are not tolerated because of side effects or concomitant diseases, and in particular in pregnancy where other therapies may not be used. IVIG cannot be recommended for treatment in secondary progressive MS. IVIG does not seem to have any valuable effect as add-on therapy to methylprednisolone for acute exacerbations and cannot be recommended as treatment for chronic symptoms in MS. In clinically isolated syndromes and in primary progressive MS, the EFNS Task Force concluded that there is not sufficient evidence to make any recommendations. 9

Similar findings were reported in a review of evidence by members of the Primary Immunodeficiency Committee of the AAAAI. The Committee concluded that IVIG might provide benefit for relapsing-remitting multiple sclerosis. 59 A meta-analysis and a review of multiple sclerosis clinical trials also found that evidence supports the use of IVIG for reduction of relapses in relapsing-remitting MS. 18 The use of IVIG in relapsing-remitting MS should only be considered when other established therapies have failed or cannot be utilized.

In their review of relapse therapy and intermittent long-term therapy, the Neuromyelitis Optica Study Group (NEMOS) suggests IVIG therapy as an alternative for patients with contraindication to one of the other treatments (azathioprine and rituximab) or, particularly, in children. 22

The use of intravenous immunoglobulin (IVIG) as treatment for acute relapses in NMO was reported in a retrospective review of 10 patients. 55 In the majority of cases, IVIG was used due to lack of response to steroids with/without plasma exchange. Improvement was noted in five of 11 (45.5%) events; the remaining had no further worsening.

In a case series of eight Spanish patients with neuromyelitis optica (NMO), positive results were observed from bimonthly IVIG treatment (0.7 g/kg body weight/day for 3 days). 56 The primary outcome measure in the study was the occurrence of serious adverse effects. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). All 8 patients were treated with IVIG; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis (LETM). The mean age of onset was 20.5 years (range, 7-31 years) and 87.5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3-17 years). Following 83 infusions (range, 4-21 per patient) and a mean follow-up time of 19.3 months (range, 6-39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z = −2.5, p=0.01). The EDSS score fell from 3.3 [SD 1.3] to 2.6 [SD 1.5] (z = −2.0, p=0.04). The investigators concluded that treatment with IVIG is safe and well- tolerated, and it may be used as a treatment alternative for NMO spectrum disorders.

Primary and Secondary Immune Deficiencies IVIG is indicated as replacement therapy in primary immune deficiencies. 6,12,14-17,21,28,31,37,42,43,59

IVIG is also beneficial in chronic lymphocytic leukemia with reduced IgG and history of infections 3,15,16,27,37 and prevention of bacterial infection in HIV-infected children. 14,23,37 IVIG is also beneficial in patients with reduced IgG and history of infections for the prevention of infection following B-cell targeted therapies. 38,45

Miscellaneous Categories Evidence supports IVIG for autoimmune bullous diseases; 3,24,27,59 toxic epidermal necrolysis and Stevens-Johnson syndrome; 59 severe, persistent, high-dose, steroid-dependent asthma; 59 delayed-pressure urticaria; 59 prevention of infection and acute GVHD after allogeneic bone marrow transplantation; 14,37,59 and prevention and treatment of acute humoral rejection in renal transplantation. 59


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Unproven Acquired Hemophilia An article by Anderson et al. summarized the National Advisory Committee on Blood and Blood Products of Canada (NAC) and Canadian Blood Services panel of national experts’ evidence-based practice guideline on the use of IVIG for hematologic conditions. In